The project will investigate the structural and functional neuroanatomy of sleep disordered breathing associated with obstructive sleep apnea (OSA), a syndrome that affects up to 4 % of the population. Our studies in the past period demonstrated that OSA and heart failure patients show significant gray matter loss in cerebellar, limbic, and cortical areas that mediate patterning of breathing, initiation of respiration following a pause, fine control of upper airway musculature, and blood pressure. With functional magnetic resonance imaging (tMRI), we also found abnormal neural responses develop to breathing and cardiovascular challenges in brain regions that overlap areas of gray matter loss. Some of the regions that showed structural and functional abnormalities in OSA receive axonal projections that are extraordinarily sensitive to hypoxemia and excitotoxicity, suggesting that certain abnormalities may resuk from repeated hypoxic episodes. Other brain sites with gray matter loss or dysfunction were unilateral or were in well-perfused areas that are less sensitive to hypoxemia, suggesting the possibility of maldevelopment or neural damage pre-existing the syndrome. We will use high resolution volumetric structural MRI and diffusion tensor MRI in OSA patients and controls to a) demonstrate axonal damage in olivo-Purkinje climbing fibers of the cerebellum and perforant path fibers to the CA1 region of the hippocampus, and b) define specific areas of gray matter loss in hippocampal, cerebellar cortex and deep nuclei, and insular, frontal and parietal cortex. Functional MRI will be used to evaluate neural responses in affected areas to a cold pressor challenge at higher spatial and temporal resolution. The studies have the potential to reveal the causative neural deficits that lead to the upper airway atonia, out-of-synchrony respiratory action, and high sympathetic tone associated with disordered breathing during sleep. The determination of axonal and gray matter loss resulting from repeated hypoxia during sleep represents a significant and necessary forward step in the development of therapeutic interventions.